A riluzole / ciprofloxacin hybrid and its derivatives as well as preparation methods and applications

Abstract

The present invention relates to a riluzole / ciprofloxacin hybrid derivative and its preparation method and anti-tumor application. Compounds LD-1, LD-2, LD-3, LD-4, LD-5, LD-6, LD-7, and LD-8 are disclosed. These compounds exhibit anti-proliferative activity against various tumor cells, with high anti-tumor cell proliferation activity, superior to that of ciprofloxacin, riluzole, and cisplatin. These compounds have potentially important roles as MST3 inhibitors in the treatment of tumors and other diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis and pharmaceutical application, and particularly relates to a riluzole / ciprofloxacin hybrid and its derivatives, a preparation method thereof, and applications thereof as an MST3 inhibitor and an anti-tumor agent. Background Art

[0002] Mammalian ste20-like protein kinase 3 (MST3), also known as serine / threonine-protein kinase STK24 (STK24), is a serine / threonine protein kinase that belongs to the mammalian ste20-like protein kinase family. MST3 is involved in regulating tumor cell proliferation, apoptosis, migration, and invasion, and activated MST3 may contribute to tumor development and progression. Currently, drug research based on MST3 inhibitors is in its infancy, and no relevant drugs have entered clinical trials. Therefore, the discovery of novel structurally active, highly selective, and potent anticancer MST3 inhibitors is of great significance. Summary of the Invention

[0003] Purpose of the invention: The present invention proposes riluzole / ciprofloxacin hybrids and their derivatives, as well as preparation methods and anti-tumor applications, to provide novel riluzole / ciprofloxacin hybrids and their derivatives with new structural types, high activity, and high selectivity, and to point out their applications in anti-tumor.

[0004] Technical solution:

[0005] The first aspect of the present invention provides a riluzole / ciprofloxacin hybrid and its derivatives, including the following compounds:

[0006]

[0007]

[0008] The second aspect of the present invention provides a method for preparing the riluzole / ciprofloxacin hybrid and its derivatives, comprising the following steps:

[0009] (1) Ciprofloxacin (Compound 1) was dissolved in water / dioxane (1:1) containing 1 M NaOH, and Boc2O was added to the solution. The mixture was stirred at room temperature (25°C) for 24 h to obtain Compound 2;

[0010] (2) Compound 2, HBTU, and DMAP (catalytic amount) were dissolved in dry DCM, and DIPEA was added. The reaction mixture was stirred at room temperature for 30 min under nitrogen protection. Riluzole and its derivatives were added to the reaction mixture, respectively, and stirred at room temperature for 12 h to obtain the corresponding compounds 3a-h;

[0011] (3) Compounds 3a-h were dissolved in DCM solution, and trifluoroacetic acid was added dropwise under ice bath conditions to obtain the corresponding compounds LD-1(4a), LD-2(4a), LD-3(4a), LD-4(4a), LD-5(4a), LD-6(4a), LD-7(4a) and LD-8(4a).

[0012] Wherein, the structural formula of compound 1 is The structural formula of compound 2 is The structural formulas of compounds 3a-h are

[0013]

[0014] Furthermore, the derivative of riluzole in step (2) is one of 6-methoxybenzo[d]thiazol-2-amine, 5-methoxybenzo[d]thiazol-2-amine, benzo[d]thiazol-2-amine, 6-methylbenzo[d]thiazol-2-amine, 4-methylbenzo[d]thiazol-2-amine, 6-chlorobenzo[d]thiazol-2-amine and 4-chlorobenzo[d]thiazol-2-amine; the structural formulas of riluzole and its derivatives in step 2 are respectively

[0015]

[0016] The third aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound or a pharmaceutically acceptable salt thereof.

[0017] The fourth aspect of the present invention provides a preparation, wherein the pharmaceutical composition is prepared by adding one or more pharmaceutically acceptable excipients to the compound.

[0018] The fifth aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug.

[0019] The sixth aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of an MST3 inhibitor.

[0020] Compared with the existing technology, the present invention has the following significant features:

[0021] 1. The compounds proposed in this invention have anti-proliferation activity against multiple tumor cells and have high anti-proliferation activity against tumor cells. In particular, compound LD-1 has the best anti-proliferation activity against tumor cells, which is far superior to ciprofloxacin, riluzole and cisplatin. High selectivity

[0022] 2. The compounds proposed in this invention have the activity and selectivity to inhibit MST3. Therefore, these compounds have the potential to play an important role as MST3 inhibitors in the treatment of tumors and other diseases.

[0023] 3. The preferred compound LD-1 of the present invention has the activity of inducing tumor cell apoptosis and inhibiting the growth of subcutaneous tumors in nude mice without obvious toxic side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Schematic diagram of the preparation method of compounds LD-1, LD-2, LD-3, LD-4, LD-5, LD-6, LD-7 and LD-8; (a) in the figure: (Boc)2O, 1M NaOH, THF, rt, 16h; (b) riluzole and its derivatives, HBTU, DMAP, DIPEA, dry DCM, rt, 6h; (c) 1:1 TFA / DCM, 0°C to rt, 6h;

[0025] Figure 2 The effect of compound LD-1 on apoptosis of HepG2 cells; A is a picture of the effect of LD-1 on apoptosis of HepG2 cells analyzed by flow cytometry, the lower left quadrant represents live cells, the lower right quadrant represents early apoptotic cells, the upper right quadrant represents late apoptotic cells, and the upper left quadrant represents necrotic cells; B is a bar graph of the proportion of apoptotic cells in each group, compared with the control group, ** represents p < 0.01, *** represents p < 0.001, **** represents p < 0.0001;

[0026] Figure 3 The selectivity profile of compound LD-1 against 217 kinases;

[0027] Figure 4 This is a photo of the tumor sample 15 days after administration;

[0028] Figure 5 is the curve of tumor volume change in each drug-treated group;

[0029] Figure 6 is the tumor weight at 15 days after administration;

[0030] Figure 7 The figure shows the body weight change curves of each drug group. DETAILED DESCRIPTION

[0031] The present invention is described in more detail below with reference to the accompanying drawings. All solvents used in the present invention are commercially available chemically pure or analytically pure.

[0032] The structure of the compound was determined by nuclear magnetic resonance (NMR). NMR measurements were performed using a Bruker AVANCE-300 / 500 NMR spectrometer, with CDCl3 or DMSO-d6 as the solvent and TMS as the internal standard. Figure 1 shown.

[0033] Example 1

[0034] 7-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (Compound 2)

[0035] Ciprofloxacin (Compound 1) (5 g, 15 mmol) was dissolved in 87.5 mL of water / dioxane (1:1) containing 22.5 mL of 1 M NaOH. Boc2O (4.91 g, 22.5 mmol) was added to the solution and stirred at room temperature (25°C) for 24 h. Three-quarters of the solvent was removed under air, and acetone (300 mL) was added to the crude reaction residue. The solid product was filtered, washed extensively with acetone, and dried under vacuum. The product was collected as a white solid (6 g, 92% yield). 1 H NMR (400MHz, CDCl3) δ8.77(s,1H),8.02(d,JH-F=12.9Hz,1H),7.35(d,J=6.8Hz,1H),3.71-3.60( m,4H),3.57-3.50(m,1H),3.35-3.25(m,4H),1.50(s,9H),1.43-1.35(m,2H),1.29-1.19(m,2H).

[0036] Example 2

[0037] 1-Cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-1)

[0038] Compound 2 (0.5 mmol), HBTU (0.6 mmol), and DMAP (catalytic amount) were dissolved in 100 mL of dry DCM, followed by the addition of DIPEA (1 mmol). The reaction mixture was stirred at room temperature under nitrogen for 30 minutes. Riluzole (1 mmol) was added and stirred at room temperature for 12 hours. After the reaction, 50 mL of the mixture was added and washed with distilled water. The organic phase was dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography to yield compound 3a. Compound 3a was dissolved in DCM (5 mL), and trifluoroacetic acid (2.5 mL) was added dropwise to the reaction mixture under stirring in an ice bath. The mixture was stirred at room temperature for 3 hours. After the complete disappearance of compound 3a (monitored by TLC), the solvent was removed under vacuum. The product was dissolved in diethyl ether and sonicated, subsequently precipitated. The resulting light yellow solid was washed with diethyl ether and dried in vacuo to yield compound LD-1 in a 66% yield. 1 H NMR(400MHz,)δ13.85(s,1H),9.42(s,1H),8.81(s,1H),8.15(d,J=2.5Hz,1H),7.98(d,J=13.1Hz,1H),7.86(d,J=8.8Hz,1H),7.60(d ,J=7.4Hz,1H),7.44(dd,J=8.8,2.5Hz,1H),3.87(dq,J=7.2,3.7Hz,1H),3.64–3.50(m,4H),1.40–1.31(m,2H),1.23(t,J=5.1Hz,2H). 13 C NMR (151MHz, DMSO-d6) δ174.8, 163.0, 162.9, 158.6, 152.9 (d, J = 248.7Hz), 148.3, 147.8, 143.7, 138.6, 133.2, 121. 1,121.7,120.4(q,J=256.2Hz),120.0,115.1,111.8(d,J=22.4Hz),107.4,46.4(2C),42.6(2C),36.4,7.7(2C).HRMS for C 25 H 22 F4N5O3S[M+H] + :calcd,548.1374; found,548.1372.

[0039] Example 3

[0040] 1-Cyclopropyl-6-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-2)

[0041] The procedure of Example 2 was repeated with 6-methoxybenzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (same as riluzole in Example 2) and other conditions remained unchanged to obtain a light yellow solid LD-2 with a yield of 66%. 1 H NMR (600MHz, DMSO-d6) δ13.68(s,1H),8.81(s,1H),8.40(br,1H),8.00(d,J=12.5Hz,1H),7.67(d,J=8.0Hz,1H),7.60(d,J=2.5Hz,1H),7.59(d,J =8.0Hz,1H),7.05(dd,J=8.0,2.5Hz,1H),3.88–3.83(m,1H),3.82(s,3H) ,3.47(t,J=4.8Hz,4H),3.28(t,J=4.8Hz,4H),1.34(m,2H),1.22(m,2H). 13 C NMR(151MHz,DMSO-d6)δ174.94,163.00,159.11,158.51,154.21,152.56,150.53,148.28,145.42,139.04 ,124.05,122.51,120.50,113.26,111.81,107.84,106.65,104.58,55.87,50.46,45.37,36.12,8.03.HRMS forC 25 H 24 FN5O3S[M+H] + :calcd,494.1657; found,494.1658.

[0042] Example 4

[0043] 1-Cyclopropyl-6-fluoro-N-(5-methoxybenzo[d]thiazol-2-yl)-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-3)

[0044] The procedure of Example 2 was repeated with 5-methoxybenzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and other conditions remained unchanged to obtain a light yellow solid LD-3 with a yield of 51%. 1H NMR(600MHz,DMSO-d6)δ13.73(s,1H),9.52(br,1H),8.79(s,1H),7.98(d,J =13.1Hz,1H),7.85(d,J=8.7Hz,1H),7.58(d,J=7.4Hz,1H),7.32(d,J=2.5Hz ,1H),6.96(dd,J=8.7,2.5Hz,1H),3.87(pd,J=6.8,3.2Hz,1H),3.83(s,3H), 3.53-5.57(m,4H),3.36–3.26(m,4H),1.43–1.35(m,2H),1.26–1.20(m,2H). 13 C NMR (151MHz, CDCl3) δ174.9, 163.6, 162.7, 155.2 (d, J = 257.9Hz), 153.53, 149.12, 145.74, 145.68, 139.41, 136.33, 123.49, 120 .43,117.76,117.52,113.04,112.88(d,J=22.6Hz),106.72,99.21,56.21,46.53,44.33(2C),44.25(2C),37.25,8.42(2C).HRMS for C 25 H 24 FN5O3S[M+H] + :calcd,494.1657; found,494.1656.

[0045] Example 5

[0046] N-(Benzo[d]thiazol-2-yl)-1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-4)

[0047] The procedure of Example 2 was repeated with benzo[d]thiazol-2-amine replacing 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and other conditions remaining unchanged to obtain a light yellow solid LD-4 with a yield of 41%. 1 H NMR (600MHz, CDCl3) δ11.94(s,1H),9.17(s,1H),8.32(br,1H),7.96(m,2H),7.99–7.89(d,J=7.8Hz,1H),7.7 5–7.59(m,3H),3.94(p,J=6.0Hz,1H),3.76-3.82(m,4H),3.66–3.57(m,3H),1.54(m,2H),1.39–1.18(m,2H). 13C NMR (151MHz, CDCl3) δ174.7, 163.8, 162.6, 154.3 (d, J = 247.4Hz), 149.1, 147.2, 145.7, 139.4, 134.8, 129.8 ,127.6,126.0,122.9,120.1,116.1,112.8(d,J=21.5Hz),106.7,46.5(2C),44.3(2C),37.3,8.3(2C).HRMS for C2H 23 FN5O2S[M+H] + :calcd,464.1551; found,464.1587.

[0048] Example 6

[0049] 1-Cyclopropyl-6-fluoro-N-(6-methylbenzo[d]thiazol-2-yl)-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-5)

[0050] The procedure of Example 2 was repeated with 6-methylbenzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and other conditions remained unchanged to obtain a light yellow solid LD-5 with a yield of 69%. 1 H NMR (600MHz, DMSO-d6) δ13.76(s,1H),9.57(dr,1H),8.80(d,J=1.8Hz,1H),7.98(d,J=12.2Hz,1H),7.77(d,J=7.7Hz,1H),7 .58(s,1H),7.46(d,J=2.5Hz,1H),7.33–7.27(m,1H),3.62–3.43(m,4H),3.31-3.22(m,4H),2.55(s,3H),1.39–1.16(m,4H). 13 C NMR (151MHz, CDCl3) δ175.0, 163.6, 161.8, 154.3 (d, J = 254.8Hz), 149.2, 145.7, 144.3, 139.5, 132.6, 131.4, 138.8, 12 6.2,122.6,120.3,115.7(d,J=22.6Hz),112.8,106.7,46.5(2C),44.3(2C),37.3,21.6,8.3(2C).HRMS:478.1710[M+H] + ,(calcd for C 25 H 25 FN5O2S,478.1708).HRMS for C25 H 25 FN5O2S[M+H] + :calcd,478.1708; found,478.1710.

[0051] Example 7

[0052] 1-Cyclopropyl-6-fluoro-N-(4-methylbenzo[d]thiazol-2-yl)-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-6)

[0053] The procedure of Example 2 was repeated with 4-methylbenzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and other conditions remained unchanged to obtain a light yellow solid LD-6 with a yield of 72%. 1 H NMR (600MHz, DMSO-d6) δ13.80(s,1H),8.76(s,1H),7.90(d,J=13.4Hz,1H),7.79(d,J=7.8Hz,1H),7.49(d,J=7.4Hz,1H),7.25(d, J=7.3Hz,1H),7.21(t,J=7.6Hz,1H),3.82(p,J=6.0Hz,1H),3.44–2.89(m,8H),2.59(s,3H),1.37–1.28(m,2H),1.25–1.19(m,2H). 13 C NMR (151MHz, CDCl3) δ175.1, 163.4, 162.4, 154.2 (d, J = 253.4Hz), 149.3, 148.3, 145.5, 139.2, 134.1, 130.7, 127.6, 126.6, 126.0, 120.4, 120.1 112.8(d,J=22.6Hz),107.2,46.6(2C),43.9(2C),37.0,17.26,8.33(2C).HRMS for C 25 H 25 FN5O2S[M+H] + :calcd,478.1708; found,478.1703.

[0054] Example 8

[0055] N-(6-chlorobenzo[d]thiazol-2-yl)-1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-7)

[0056] The procedure of Example 2 was repeated with 6-chlorobenzo[d]thiazol-2-amine replacing 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and other conditions remaining unchanged to obtain light yellow solid LD-7 in a yield of 27%. 1 H NMR (600MHz, DMSO-d6) δ13.87(s,1H),9.28(br,1H),8.83(s,1H),8.17(d,J=2.1Hz,1H),8.02(d,J=13.1Hz,1H),7.78(d,J= 8.4Hz,1H),7.62(d,J=7.4Hz,1H),7.52–7.46(m,1H),3.88(m,1H),3.38-3.31(m,4H),1.38-1.33(m,2H),1.25–1.19(m,2H). 13 C NMR (151MHz, CDCl3) δ175.2, 163.9, 162.8, 153.4 (d, J = 257.9Hz), 149.1, 147.9, 145.5, 139.4, 133.8, 133.5, 13 1.8,128.1,122.6,121.3,120.2,113.0(d,J=22.2Hz),106.76,47.9(2C),44.3(2C),37.33,8.41(2C).HRMSfor C 24 H 22 ClFN5O2S[M+H] + :calcd,498.1161; found,498.1150.

[0057] Example 9

[0058] N-(4-chlorobenzo[d]thiazol-2-yl)-1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-8)

[0059] The procedure of Example 2 was repeated with 4-chlorobenzo[d]thiazol-2-amine replacing 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and other conditions remaining unchanged to obtain light yellow solid LD-8 with a yield of 51%. 1H NMR (600MHz, CDCl3) δ11.44(s,1H),9.02(s,1H),8.19(s,1H),7.88(d,J=12.3Hz 1H),7.79(d,J=8.3Hz,1H),7.64(d,J=7.7Hz,1H),7.58(s,1H),7.50(t,J=8.0Hz,1H), 3.84(p,J=6.0Hz,1H),3.68(m,4H),3.55(m,4H),1.47–1.38(m,2H),1.25–1.19(m,2H). 13 C NMR (151MHz, CDCl3) δ174.1, 162.9, 162.7, 153.5 (d, J = 257.9Hz), 148.6, 145.0, 138.6, 132.1, 128.8, 127.6 ,126.7,125.9,120.7,120.1,119.4,112.07(d,J=22.6Hz),106.1,45.7(2C),43.6(2C),36.4,7.6(2C).HRMS for C 24 H 22 ClFN5O2S[M+H] + :calcd,498.1161; found,498.1161.

[0060] Example 10: Evaluation of the anti-tumor cell proliferation activity of the target compound

[0061] The cells were seeded into 96-well plates (3×10 3 ) and incubated overnight. Different concentrations of compounds were then added and incubated for 72 hours. Afterwards, 20 μL of 10% MTT (5 mg / mL, PBS) reagent was added to each well and incubated in the incubator for another 4 hours. The supernatant was then discarded, and 100 μL of DMSO was added and shaken for 8 minutes. The absorbance of the cells was measured at 490 nm on a microplate reader. Percent growth inhibition = 100–100 × (OD 样品 -OD 空白 ) / (OD 对照 -OD 空白 GI was calculated using nonlinear regression analysis (percent growth versus concentration). 50 The results are shown in Table 1. The results show that most of the riluzole / ciprofloxacin hybrids and their derivatives have moderate anti-tumor cell proliferation activity. In particular, compound LD-1 has the best anti-tumor cell proliferation activity.

[0062] Table 1 Activity of target compounds in inhibiting tumor cell proliferation

[0063]

[0064]

[0065] a GI 50 The values ​​are the 50% inhibition concentrations after drug treatment for 72 hours. All values ​​are expressed as m±SEM. The experiment was repeated three times, and three replicate wells were used for each concentration in each experiment. b Liver cancer, c colon cancer, d Lung cancer.

[0066] Example 11: Effect of LD-1 on apoptosis of HepG2 cell line

[0067] Annexin V-FITC and PI methods were used to evaluate the apoptotic effect of compound LD-1 on HepG2 cell lines. Figure 2 After 24 hours of treatment with 0.5 μM, 1.0 μM, and 2.0 μM LD-1, the percentages of apoptotic cells were 24.2%, 28.1%, and 64%, respectively. These results demonstrate that LD-1 can induce apoptosis in HepG2 cells in a concentration-dependent manner. Other compounds exhibited similar effects and are not discussed here.

[0068] Example 12: Evaluation of the target compound's ability to inhibit MST3 enzyme activity

[0069] Mobility shift assay was used, and Sunitinib was used as the reference standard. IC values ​​of LD-1 to LD-8 for inhibition of MST3 activity were 50 The values ​​are shown in Table 2. From the results, it can be seen that most compounds have good MST3 inhibitory activity, among which compounds LD-1 and LD-3 have better inhibitory activity against MST3.

[0070] Table 2 Evaluation of target compounds' inhibition of MST3 enzyme activity a

[0071]

[0072] a For one experiment, each concentration was tested in duplicate.

[0073] Example 13: Inhibitory activity of LD-1 against 217 kinases

[0074] To investigate the selectivity of the compound for MST3, we selected LD-1 for kinase profiling. At a concentration of 1 μM, the inhibition of LD-1 against 217 kinases was as follows: Figure 3As shown in Table 3. The results showed that the inhibition rate of LD-1 on MST3 at a concentration of 1 μM was 95.49%, while the inhibition rate on AKT2, which ranked second, was only 66.52%. The inhibition rates on YSK1, MST1, and MST2, which had higher homology, were 8.64%, 27.06%, and <1.00%, respectively. It can be seen that LD-1 has a high selectivity for MST3.

[0075] Table 3 Inhibition of 217 kinases by LD-1 a

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] a: One experiment, two replicate wells.

[0083] Example 14: Effects of LD-1 on subcutaneous tumor-bearing nude mice.

[0084] Based on the above experimental results, we selected LD-1 for in vivo tumor growth experiments (other compounds also have the potential to inhibit tumor growth in vivo). Other compounds have similar effects and will not be repeated here. Each mouse was injected with 200 μL (1×10 7 7 days after injection of a cell suspension of HepG2 cells suspended in 50% PBS, the tumor volume of the mice reached about 100 mm 3 Tumor-bearing mice were randomly divided into 3 groups (n=5) according to tumor volume, and 0.9% NaCl, Sorafenib (40 mg / kg) and LD-1 (40 mg / kg) were administered orally. The mice were weighed at a fixed time every day, and the tumor volume was measured with a vernier caliper. The measurement formula of tumor volume is: tumor volume (mm 3 )=(length×width 2 ) / 2, relative tumor volume (RTV) = tumor volume on day 15 / tumor volume on day 0, relative tumor volume inhibition rate (TGI) = (RTV tumor volume of drug group / RTV tumor volume of control group) × 100%. Figure 4 The following are photos of tumor samples taken 15 days after drug administration. Figure 5Figure 2 is the tumor volume change curve of each group. The TGI of Sorafenib (40 mg / kg) group and LD-1 (40 mg / kg) group were 32.52% and 47.64%, respectively. Figure 6 The tumor weight of each group was 15 days after administration. There was statistical significance between the LD-1 group and the control group (p<0.05). Figure 7 The body weight change curves of each group. Figures 4 to 6 It shows that LD-1 has a good effect in inhibiting the growth of subcutaneous tumors. Figure 7 This shows that LD-1 has no significant effect on the body weight of nude mice and has a certain degree of safety.

[0085] In summary, the riluzole / ciprofloxacin hybrid and its derivatives proposed in the present invention can be used to prepare anti-tumor drugs, and the dosage forms of the drugs include but are not limited to tablets, powders, pills, granules, capsules, solutions, suspensions or injections.

[0086] The embodiments described above are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the scope of protection determined by the claims of the present invention.

Claims

1. A riluzole / ciprofloxacin hybrid and its derivatives, characterized in that: Includes the following compounds: 。 2. A method for preparing the riluzole / ciprofloxacin hybrid and its derivatives according to claim 1, characterized in that: The steps are: (1) Dissolve ciprofloxacin in water / dioxane containing 1 M NaOH, add Boc2O to the solution, and stir at room temperature to obtain compound 2; (2) Compound 2, HBTU and DMAP were dissolved in dry DCM, DIPEA was added, and the reaction mixture was stirred at room temperature under nitrogen protection. Riluzole or its derivatives were added to the reaction mixture and stirred at room temperature to obtain the corresponding compounds 3a-h; the structural formulas of the riluzole and its derivatives are 、 、 、 、 、 、 、 ; (3) Compounds 3a-h were dissolved in DCM solution, and trifluoroacetic acid was added dropwise under ice bath conditions to obtain the corresponding compounds LD-1, LD-2, LD-3, LD-4, LD-5, LD-6, LD-7, and LD-8.

3. A pharmaceutical composition, characterized in that Contains pharmaceutically acceptable excipients and the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. A preparation, characterized in that A preparation prepared by adding one or more pharmaceutically acceptable excipients to the compound as claimed in claim 1.

5. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of anti-tumor drugs.

6. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an MST3 inhibitor.

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